Objective: Pancreatic ductal adenocarcinoma is an aggressive tumor with short survival. In this study we aimed to investigate the effect of
well-known prognostic parameters on survival in these tumors.

Material and Method: A total of 56 pancreatic ductal adenocarcinoma cases diagnosed between 2005 and 2014 were included in the study.
Survival data were obtained and histopathological parameters were re-evaluated in each patient.

Conclusion: Our results showed that existent 2010 WHO pancreatic ductal adenocarcinoma grading parameters excluding mitotic count are
subjective and not applicable. Considering that almost all of the tumors in our series were larger than 2 cm, we think that the 2 cm cut-off in
tumor size is insufficient to make the tumor stage pT2. Peripancreatic soft tissue invasion, which is a common finding in pancreatic ductal
adenocarcinoma, should also not be assessed like adjacent tissue invasion and make the tumor reach pT3 stage independent of tumor size. It is
clear that the existent WHO tumor grading and pT staging parameters need to be revised and the mitotic count, which correlates with survival,
should be presented in pathology reports.

Pancreatic ductal adenocarcinoma (PDAC), representing
the majority (80-90%) of pancreatic neoplasia, is the fourth
leading cause of cancer-related deaths. Unfortunately,
these tumors tend to present with non-specific symptoms
and generally in advanced stages. High recurrence and
metastatic capacity support the aggressiveness and high
mortality rates in these tumors (1, 2). The most important
prognostic parameter is total resection of the tumor.
However, only 10-20% of the patients have surgically
resectable tumors at the time of diagnosis (3, 4). Even in
patients who undergo total resection, the overall survival
only increases from 3-5 months to 10-20 months (3, 5).

It has been shown that tumors smaller than 3 cm and
limited to the pancreas have a better prognosis than larger
or extensive tumors (6-8). Tumor size and extension beyond
the pancreas already constitute the basic parameters of
the existing pT stage (1). Another basic factor for PDAC
prognosis is lymph node metastasis which constitutes pN
staging. Most of the studies about lymph node metastasis in PDACs have reported that the metastatic lymph node
ratio is more important than the presence of lymph node
metastasis regarding the prognosis (9-15).

Although not taking part in pT or pN staging, it has been
indicated that tumor grade, histologic subtype, mitotic
count, vascular invasion, and perineural invasion also affect
survival in PDACs (5, 16-21).

In our study, we investigated the effects of histologic and
staging parameters on survival in PDACs. We aimed
to show how these parameters reflect survival in these
aggressive tumors.

Patient and Specimen Characteristics
A total of 56 pancreatic ductal adenocarcinoma cases
that were diagnosed between 2005 and 2014 at the
Ankara University Pathology Department were evaluated.
Pancreatectomy specimens were either Whipple or distal
pancreatectomy materials. Ethical approval was obtained
from the institute’s ethics committee (Ref No. 18-766-14).

Clinical data including age, gender, additional therapy
and overall survival were obtained from the hospital’s
database system. In each case, Formalin-fixed, paraffinembedded
(FFPE) tissues representing the whole tumor
were sectioned into 4μm thick slices and H&E stained in
order to re-evaluate the pathological data as tumor grade,
mitotic activity, lymphovascular and perineural invasion,
lymph node metastasis and resection margin status.

Grading the Tumors
All the tumors were re-evaluated according to the WHO
2010 PDAC grading criteria shown in the Table I (1).

Statistics
‘SPSS for Windows 11.5’ was used for data collection and
statistical analysis. The Kaplan-Meier survival curve was
estimated and the log-rank test was used to compare the
survival. A p-value <0.05 was considered statistically
significant.

Patients, Operations and Follow-Up
A total of 108 patients received a PDAC diagnosis between
2005 and 2014 at our department. Treatment and survival data were obtained from 60 of them. Four patients who
died due to surgical complications were excluded from the
group and 56 patients were included in the study. The mean
age was 63.9 years (range 44-83 years) and the patients had
a male predominance with a ratio of 1.9:1 (male, n=37;
female, n=19). The majority of the patients (66.1%) had
undergone the Whipple operation and more than half of
the tumors (53.5%) were localized in the pancreatic head.
The ratio of patients treated with adjuvant chemotherapy
was 80.3% while 48.2% received radiotherapy. Three liver
metastases and one omentum metastasis were proven by
histopathological examinations. 42.9% of the patients had
radiologically diagnosed metastasis and the liver constituted
the majority of the suspected areas (28.5%). During the
study, 48 patients died and the mean overall survival was
15.7 months (range 1-49 months) (Table II).

The mean tumor size was 4.4 cm (range 2-8.5 cm) and the
distribution was as follows: 78.6% had a diameter >3 cm,
16.1% 2-3 cm and 5.3% ≤2 cm (Figure 1). The majority of
the tumors (69.6%) were Grade II, 28.6% were Grade III
and only 1.8% were Grade I (Figure 2- 4). The mitotic rate
was ≤5/HPF (x400 magnification) in 51.8% of the tumors,
6-10/HPF in 32.1% and >10/HPF in 16.1% (Figure 5).

The number of mitoses showed a more balanced distribution
than the tumor grade. Among the cases, 91.1% of the tumors
had perineural and 39.3% had lymphovascular invasions.
The average number of dissected lymph nodes was 10.53
and 10% were metastatic.

PDACs which have high capacity of invasion and metastasis
are generally diagnosed in advanced stages. These tumors
are the fourth leading cause of death among all cancers in
the United States. 5 year survival rates raise from 3-5% to
15-25% only after complete resection (1). The percentage of
male patients in our group was 66.1% and the average age
63.9 years. Nearly half of the tumors (53.5%) were localized
in the pancreatic head. The average tumor size was 4.4 cm
and the majority of them (78.5%) were larger than 3 cm
in diameter. Perineural invasion was a common finding
(91.1%). Average number of dissected lymph nodes was
10.5 and the metastatic rate was 10%. Peripancreatic soft
tissue invasion (86%) was the most commonly observed
adjacent tissue invasion in our series. Mean survival was
15.7 months. There was a remarkable fall in survival after
first year. All these findings were parallel with the literature
and prior studies (1, 3, 5, 6, 11).

Tumor grade is one of the commonly accepted prognostic
factors in PDAC. However, we could not find any
statistically significant relationship between the tumor
grade and survival in our series. Moreover, there was no
homogeneous distribution among tumor grade groups
in our series. On the other hand, a statistically significant
correlation between the mitotic count and the survival
was found (p=0.030). Except for mitotic count, WHO
tumor grading parameters of PDACs such as mucin
production, glandular differentiation, and nuclear features
are subjective. Therefore, grading these tumors with these
parameters is not applicable and causes interobserver
variability. Conflicting results have been reported about
the relation between tumor grade and survival in various
studies. Some studies reported that tumor grade was
significantly related to survival (9, 22, 23) whereas some
studies declared that existent grading parameters cause
interobserver variability (24, 25). Therefore, tumor grading
parameters in PDACs must be revised and mitotic count
which has significant correlation with survival should be
specified in the pathology reports (as <5, 6-10, >10).

After grouping the tumors according to the tumor size (≤3
cm and >3 cm), shorter survival was found in tumors >3 cm
(p=0.029). Tumor size is already one of the parameters in
existent pT staging. Tumors greater than 2 cm are assessed
in pT2 stage for tumors limited to the pancreas (1). However,
tumors tend to have larger sizes and 2 cm cut-off is not
sufficient in pT staging in these tumors. Even in our series,
there was no tumor smaller than 2 cm. This problem would
be solved by the recently published AJCC Cancer Staging
Manual 8th edition which recommends discriminating pT2
(2-4 cm) and pT3 (>4 cm) with the tumor size (26). The
effects of new cut-offs on survival would be investigated in
new studies with large series.

In our series, peripancreatic soft tissue invasion had no
relationship with survival. However, in the 2010 WHO
TNM classification, all tumors showing peripancreatic soft
tissue invasion are evaluated in the pT3 stage, independent
of tumor size. The fact that the pancreas is located in fatty
tissue without a capsule makes it difficult to distinguish
the peripancreatic soft tissue border. Moreover, similar to our findings, peripancreatic soft tissue invasions have been
usually observed in PDACs even in the early stages (27).
Also, the superiority of tumor size to peripancreatic soft
tissue invasion as a prognostic factor has been shown in
various studies (28, 29). Recently, extrapancreatic extension
is no longer a part of pT3 definition in AJCC Cancer Staging
Manual 8th. edition (26).

Existence of lymph node metastasis (p=0.003) and
metastatic lymph node ratio (p<0,001) had a statistically
significant relationship with survival in our study. Existence
of lymph node metastasis, independent from metastatic
lymph node number is sufficient to indicate pN stage pN1
(1). In some studies, it has been reported that metastatic
lymph node ratio is more important than only the presence
of lymph node metastasis on survival (9, 11, 12, 30, 31).
There are also important changes regarding the pN stage
in the recently published AJCC Cancer Staging Manuel
8th edition. In this edition, the N stage is subdivided into
N1 (≤ 3) and N2 (> 3) groups according to the number of
metastatic lymph nodes (26).

In conclusion, our study showed that well known
prognostic parameters like tumor grade and peripancreatic
soft tissue invasion did not have any significant relationship
with survival. As mitotic count showed a statistically
significant correlation with survival, it should be presented
in pathology reports. Most of the problematic issues (tumor
size, peripancreatic soft tissue invasion and pN stage) we
discussed in this study already underwent fundamental
changes with the recently published AJCC Cancer Staging
Manual 8th edition. We look forward to hearing changes
about tumor grading parameters that can make the grading
of PDACs more relevant.